Pathways of nucleic acid metabolism and innate immune sensing (WP4705)

Homo sapiens

Cytosolic DNA and RNA can lead to innate immune sensing via three paths. DNA is sensed by cGAS, which activates STING. RNA is sensed by MDA5 and RIG-I, which activates MAVS. An activation of STING or MAVS lead to phosphorylation of IFR3, which triggers innate immune responses. This pathway was inspired by Chapter 14 of the 5th edition of the book of Blau (in press).


Denise Slenter , Laurent Winckers , Egon Willighagen , and Eric Weitz


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Homo sapiens


Inherited Metabolic Disorders (IMD) Pathways


Pathway Ontology

signaling pathway in the innate immune response altered DNA repair pathway


Label Type Compact URI Comment
dNTP pools Metabolite chebi:61560
Adenosine Metabolite chebi:74411
dN Metabolite chebi:18274
Inosine Metabolite chebi:82852
IFIH1 GeneProduct ensembl:ENSG00000115267
DDX58 GeneProduct ensembl:ENSG00000107201
IFNB GeneProduct ensembl:ENSG00000171855
TMEM173 GeneProduct ensembl:ENSG00000184584 cGAS which signals via STING (encoded by TMEM173)
RNase T2 Protein uniprot:O00584
SAMHD1 Protein uniprot:Q9Y3Z3
STING Protein uniprot:Q86WV6
RNase H2subunit A Protein uniprot:O75792 Catalytic subunit
TREX1 Protein uniprot:Q9NSU2 Cytosolic deoxyribonuclease anchored in the outer nuclear membrane. A lack of TREX1 causes DNA accumulation, both within the nucleus and the cytosol.
OAS1 Protein uniprot:P00973
RNase L Protein uniprot:Q05823
ADAR Protein uniprot:P55265 Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing
cGAS Protein uniprot:Q8N884 DNA sensor
MAVS Protein uniprot:Q7Z434 mitochondrial antiviral signaling (MAVS)
IRF3 Protein uniprot:Q14653
MDA5 Protein uniprot:Q9BYX4 Cytosolic RNA sensor
Activating mutations in RIG-I and MDA5 increase receptor affinity resulting in constitutive type I IFN signaling.
RIG-I Protein uniprot:O95786 cytosolic RNA sensor
Activating mutations in RIG-I and MDA5 increase receptor affinity resulting in constitutive type I IFN signaling.
RNase H2subunit B Protein uniprot:Q5TBB1 Noncatalytic subunit
RNase H2subunit C Protein uniprot:Q8TDP1 Noncatalytic subunit
SAMHD1 Protein uniprot:Q9Y3Z3 SAMHD1 has also ribonuclease activity, suggesting that a loss of SAMHD1 may lead to RNA accumulation.
IRF3 Protein uniprot:Q14653
ISGs Protein interpro:IPR000471 interferon-responsive genes


  1. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Patterson JB, Samuel CE. Mol Cell Biol. 1995 Oct;15(10):5376–88. PubMed Europe PMC Scholia
  2. Mammalian retroelements. Deininger PL, Batzer MA. Genome Res. 2002 Oct;12(10):1455–65. PubMed Europe PMC Scholia
  3. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. Cho DSC, Yang W, Lee JT, Shiekhattar R, Murray JM, Nishikura K. J Biol Chem. 2003 May 9;278(19):17093–102. PubMed Europe PMC Scholia